Adverse effects of cocaine, particularly on the cardiovascular system, are important clinical concerns. Although physiological changes after experimenter-administered cocaine have been investigated extensively, the corresponding changes to self-administered cocaine are largely unknown. Since environment and the ongoing behavior of the subject can influence physiology, it is of clinical relevance to study physiological changes that occur in subjects self-administering cocaine. The goals of this project are to characterize the physiological changes associated with cocaine self-administration and to evaluate the effects of potential treatment drugs for cocaine addiction on these changes. The objectives are: 1) to characterize the physiological changes to cocaine self- administration; 2) to compare the physiological changes to self- administered cocaine with that of investigator-administered (yoked) cocaine; 3) to determine the role of classical conditioning mechanisms in the differential physiological responses to cocaine in self- administering versus yoked animals; 4) to identify the functional changes in the cardiovascular system produced by cocaine self-administration; 5) to test the effects of potential treatment drugs on the physiological changes produced by self-administered cocaine. These studies will be performed in rats and squirrel monkeys implanted with transmitters that are designed to transmit information telemetrically about blood pressure, heart rate, ECG, temperature and motor activity. The hypothesis is that the physiological changes to self-administered cocaine are not identical to those produced by yoked cocaine. There may be some critical physiological changes in individuals self-administering cocaine that may make them susceptible to sudden fatalities. Specific aim 1 examines the changes in diastolic, systolic and mean blood pressures, heart rate, cardiac rhythm, PR, QRS, QT and QA intervals, plasma catecholamines, body temperature and motor activity in response to cocaine self-administration in rats. Specific aim 2 investigates the effects of cocaine injections in yoked control rats on the above parameters and compares them with effects in rats self-administering cocaine. Specific aim 3 determines the potential importance of classical conditioning mechanisms in any differences in physiological responses to cocaine in self-administered versus yoked rats. Specific aim 4 characterizes the functional changes in the cardiovascular system produced by cocaine self-administration using various in vivo functional tests in rats. Specific aim 5 tests the effects of various potential treatment drugs for cocaine addiction on the physiological changes produced by self-administered cocaine in rats. Specific aim 6 determines the physiological changes during cocaine self- administration in nonhuman primates, squirrel monkeys, and evaluates the possible classical conditioning mechanisms involved. These studies should provide fundamental new information on issues of significant relevance to human cocaine abuse and its associated adverse physiological consequences. These studies should also aid in the preclinical safety evaluation of drugs that are proposed for the treatment of cocaine addiction.